Triacylglycerols (TAGs) are important energy-storage molecules which can be found in almost all eukaryotes. In mammals, TAG synthesis plays essential roles in a number of physiological processes, including intestinal fat absorption, energy storage in muscle and adipose tissue and lactation. TAG synthesis also contributes to pathological conditions such as obesity and hypertriglyceridemia (1).
TAG synthesis by the glycerol-3-phosphate pathway and the monoacylglycerol pathway is acyl-CoA dependent. The transfer of an acyl group from acyl-CoA to diacylglycerols (DAGs) catalyzed by the enzyme diacylglycerol acyl-transferase (DGAT) is regarded as the only committed reaction in TAG synthesis in the glycerolipid pathway, since DAGs are diverted from membrane glycerolipid biosynthesis (2).
Two distinct mammalian DGAT genes have been identified recently. DGAT1 was cloned based on its sequence homology to genes involved in sterol esterification (3, 4). DGAT2 was identified by its homology to a DGAT isolated from the fungus Mortierella rammaniana (5, 6). Other acyl-CoA dependent TAG synthesizing enzymes are likely present but are yet to be identified. In addition, acyl-CoA independent TAG synthesis was also shown to exist in eukaryotes. A DAG transacylase, which synthesizes TAG from two DAGs, was purified from rat intestinal microsomes and its activity was comparable to the activities of DGAT1 and DGAT2 (7).
In a recent study, mice lacking partial ability to synthesize TAGs were resistant to diet induced obesity, most probably due to increased energy expenditure (53).
Inhibitors of a mammalian diacylglycerol acyl-transferase gene DGAT1 and possibly other similar enzymes thus represent exciting novel drugs which might be useful to treat or prevent obesity (54). To date, few effective therapies are available for people suffering from obesity.
A further study has proven that synthesis of TAGs prevents fatty acid-induced lipotoxicity in mammalian cells (12). Lipotoxicity refers to the toxic effect that circulating excess fatty acids (for example in the form of diacylglycerols) have on certain non-adipose cells and tissues, particularly liver, muscle, and pancreatic beta cells, and is often seen in Type II diabetes patients (55). The effects of lipotoxicity depend on the particular cell type, and include induction of insulin resistance, for example in smooth muscle cells, and cell death (termed lipoapoptosis), for example in beta cells.
Overload of TAGs and fatty acids in non-adipose tissues, e.g. pancreas, heart, muscle, could damage those tissues by a inducing lipoapoptosis. Death of pancreatic beta cells is key to the pathogenesis of type II diabetes while death of cardiomyocytes could lead to heart failure. To date, our understanding of the molecular mechanisms underlying lipoapoptosis is limited and no therapy exists to prevent or slow down lipoapoptosis.
There is no simple yet powerful model system for developing anti-lipoapoptosis therapies to treat Type R diabetes and cardiomyopathy. A TAG-deficient budding yeast strain and a knock-out mouse strain with reduced TAG in certain tissues exist but neither showed any phenotypic relevance to lipoapoptosis.